How hepatitis C virus invades hepatocytes: The mystery of viral entry

Table 1 Characterization and the main function of cell surface molecules required for hepatitis C virus entry

	Characterization	Main function in HCV entry
GAGs	Binding factor	Attachment to HCV E1 and ApoE
LDL-R	Binding factor	Binding to virion-associated lipoprotein
SR-BI	Receptor	Binding to virion-associated lipoprotein; lipid transfer; binding to E2 HVR1
CD81	Receptor	Interaction with E2; signaling pathway activation which promotes actin remodeling
CLDN1	Receptor	Interaction with HCV-CD81 complex
OCLN	Receptor	Function at the late stage of HCV entry
EGFR and EphA2	Entry factor	Signaling pathways activation which lead to the formation of CD81-CLDN1 complexes
TfR1	Entry factor	Possibly involved in virus internalization
NPC1L1	Entry factor	Possibly involved in endosomal fusion

HCV: Hepatitis C virus; GAGs: Glycosaminoglycans; LDL: Low-density lipoprotein; CLDN1: Claudin-1; OCLN: Occludin; EGFR: Epidermal growth factor receptor; EphA2: Ephrin receptor A2; TfR1: Transferrin receptor 1; NPC1L1: Niemann-Pick C1-like 1.

Table 2 Antiviral agents targeting viral entry

Stages of HCV entry process	Target	Antiviral agents	Ref.
HCV particle/attachment	HCV E1 and E2	Neutralizing antibodies	[102,103]
		Heparin	[41,55]
		Lectins	[106,107]
		EGCG	[109,110]
		Oleanane-type triterpenes	[111]
	Virion-associated lipoprotein	Anti-apoE mAb	[108]
Receptor-mediated endocytosis	SRBI	Anti-SR-BI mAb	[113]
		ITX 5061	[117]
	CD81	Anti-CD81 mAb	[114]
	CLDN1	Anti-CLDN1mAb	[115]
		CLDN1-derived peptide	[116]
	EGFR	Erlotinib	[50]
	NPC1L1	Ezetimibe	[52]
	TfR1	Anti-TfR1 mAb	[51]
	Internalization	Amphipathic DNA polymers	[118]
		Arbidol	[122]
		Tamoxifen	[123]
Endosomal fusion	Fusion	E2-derived peptide	[121]
		CD81-derived peptide	[124]
		Curcumin	[125]
		Phenothiazines	[126]
		Ferroquine	[127]
		aUY11	[128]
		HCV II-1/GS-563253	[129]
Regulation	Ras	Tipifarnib	[78]
	PKA	H89	[96]
	MKNK1	RO4475417	[93]
	PI3K	Wortmanin	[99]

Targets within the different stages of Hepatitis C virus (HCV) entry process are depicted, followed by examples of compounds targeting the respective entry step. Stages of development and references are indicated. GAGs: Glycosaminoglycans; CLDN1: Claudin-1; OCLN: Occludin; LDLR: Low-density lipoprotein receptor; EGFR: Epidermal growth factor receptor.